1. Field of the Invention
The present invention relates to a self-adhesive polymer matrix composed of a polymer which is gel-forming in water, preferably a polyacrylic acid polymer, water, sea algae extract, and a monohydric or polyhydric alcohol. The matrix may be doped with hydrophilic or else hydrophobic active substances.
2. Discussion of Background Information
The mechanism of action of patches for administering pharmaceutical substances into the skin is subject to a functional principle similar to that of transdermal therapeutic systems (TTS).
Transdermal therapeutic systems for delivering active substances into and/or through the skin have been known for a long time and constitute patch-like systems which in particular are doped with drugs.
The topical administration of drugs via active substance patch systems offers two main advantages:                First, this administration form produces first-order release kinetics of the active substance, thereby allowing a constant level of active substance to be maintained in the body over a very long period of time.        Secondly, the path of uptake through the skin avoids the gastrointestinal tract and also the first pass through the liver. As a result, selected drugs can be administered effectively in a low dose. This is particularly advantageous when it is desired that the drug should act locally, avoiding a systemic effect. This is the case, for example, with the treatment of rheumatic joint complaints or muscular inflammation.        
The time-dependent release of the substance, the drug for example, from a TTS takes place in dependence on its TTS/skin partition coefficient and its diffusion in the region of the TTS and of the skin.
Both factors are determined by the composition of the matrix, thereby allowing the amount released per unit time and the duration of activity to be influenced directly. Normally hydrocolloids, solubilizers and enhancers are used for this purpose, allowing improved solubility and diffusion and also a more rapid passage of the substance from a TTS into the skin.
Ideally, first-order release kinetics are achieved, allowing the release of equal quantities per unit time.
One embodiment of such transdermal systems which has been well described in the technical literature is that of matrix systems or monolithic systems in which the drug is incorporated directly into the pressure-sensitive adhesive. In the ready-to-apply product a pressure-sensitive adhesive matrix of this kind, comprising active substance, is equipped on one side with a backing, which is occlusive for the active substance, while on the opposite side there is a backing film equipped with a release layer, which is removed prior to application to the skin (kleben&dichten, No. 42, 1992, pp. 26 to 30).
The aforementioned properties of a TTS avoid the need for frequently repeated administration and avoid burdening the skin with high concentrations of active substances, and so reduce irritation to the skin, which is unavoidable in the event of repeated administration of liquid and semisolid administration forms. If, nevertheless, unwanted effects occur in the course of a TTS application, further burdening can be halted immediately by removing the TTS.
In summary, the advantages of the TTS lie in a distinctly improved compliance on the part of users, which is attributable to the simple and rapid administration and to the long-lasting efficacy of transdermal therapeutic systems.
One basic requirement of a TTS is effective adhesion to skin, which must be maintained over the entire period of the intended dosing of active substance, and another is the ability for the TTS to be removed without residue. Painful redetachment of the active substance patch after a prolonged period of wear is a frequent observation. As well as adhesives which are coated in solution onto the backing, the adhesives used also include solvent-free systems, such as hot-melt adhesives. A feature of these adhesives is that in the course of their coating it is possible to forego the use of organic solvent and dispersion medium. Hot-melt adhesives are converted to a liquid form by heating and are applied thus as a melt to the respective patch backing. As well as technical aspects, such as solvent processing, plant design with anti-explosion measures, and environmental protection strictures, medical reasons as well play a part in the choice of solvent-free adhesives.
Transdermal therapeutic systems are generally applied to healthy, intact skin. Here in particular it is especially important not to irritate, let alone damage, the skin by a drug product. One frequently observed side-effect is the appearance of skin irritations, which appear in particular when a TTS is applied for a prolonged period, or repeatedly, to the same region of the body. Irritations of this kind are caused primarily by the ingredients of the pressure-sensitive adhesive matrix. In the case of solvent-borne systems it is possible following the extraction of the solvents to recover a residual amount, which on the basis of its allergenic potential may likewise lead to unwanted skin irritations. For application to skin, therefore, solvent-free systems whose formulations include, in particular, skin-friendly ingredients are to be preferred above all.
Self-adhesive matrix systems for administering active pharmaceutical and/or cosmetic substances are among traditional applications in Asia, particularly in Japan, and are defined in the Japanese pharmacopoeia under the terms “cataplasm”. Cataplasms, accordingly, are commonly prepared by mixing glycerin, water or other suitable liquids with finely pulverized active substances, with the addition of essential oils.
Glycerin functions here as a humectant, in order to prevent the cataplasms from drying out prematurely in use.
Whereas in the traditional Asian preparations natural thickeners such as alumina, etc., are employed, recent decades have seen the use, more and more, of modern synthetic raw materials, such as polyacrylic acid as a gel former, for example, for their production. This allows the cataplasms, which are commonly pasty, to be produced as hydrogel matrices having improved attractiveness and user-friendliness.
EP 1 136 057 describes an aqueous gel system for cosmetic use without backing or liner, with a light transmittance of min. 70%.
EP 0 507 160 describes cataplasms containing lidocaine.
A disadvantage of the cataplasms described is that the production of the base matrices requires many different individual components such as gel formers, thickeners, plasticizers, humectants, stabilizers, emulsifiers, pH regulators, antioxidants, etc., and possibly also solubilizers and penetration enhancers in the case of active substance cataplasms. Since the adhesive performance and consistency of such a matrix is a function of the interaction of all of the individual components, targeted product development/optimization with regard to these fundamental product requirements is, correspondingly, time-consuming and arduous.
The production of polymer matrices, especially gel matrices, from polyacrylates has likewise been known for many years and is described for example in. EP 0 507 160, JP 11-228340 and JP 04178323. Gel matrices are used, among other things, as an adhesive base and as an active substance reservoir in transdermal systems. Such systems have an adequate bond strength, especially to moist skin (buccal patches), but because of inadequate cohesiveness cannot be removed again completely when required.
In order to form a gel with a defined structure it is necessary for polyacrylic acid to be cross-linked. The nature of the cross-linker makes a critical contribution to the structure of the resultant gel. The customary cross-linking agents may be metal ions (e.g.: Al3+ ions), or organic compounds. Cross-linking with aluminum salts proceeds via the coordination of the oxygen functions of the polyacrylic acid to the Al3+ ions. A very close-meshed gel with high viscosity is formed, the viscosity of the gel being controllable only via the amount of cross-linker (Handbook of Pressure Sensitive Technology, page 458 ff, 1999).
JP 11-228340 discloses polyacrylic acid-based gels which utilize Al+3 compounds as cross-linkers. The use of the mandatory aluminum compound as a cross-linking agent is limited, since otherwise the physical properties of the gel are impaired. If the proportion of aluminum cross-linker is too high the gel becomes too hard.
Known from the literature are further examples of cross-linking with polyvalent metal ions, e.g., U.S. Pat. No. 3,900,610 (zinc salts), U.S. Pat. No. 3,770,780 or U.S. Pat. No. 3,790,533 (titanium compounds). Ionic cross-linking with metal ions leads to hard, viscous polymer gels with low tack (Handbook of Pressure Sensitive Adhesive Technology, page 458 ff, 1999).
EP 303445 discloses a patch with a monolithic gel matrix based on water-soluble polymers. Mandatory constituents are clebopride or a pharmaceutically acceptable salt thereof as active substance, water, water absorbers, and water-soluble polymers. As water-soluble polymers the skilled worker is able to select from a range of known polymers such as polyvinyl alcohol, gelatin, polyacrylic acid, sodium polyacrylates, methylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, rubber and other cross-linkable polymers and also mixtures thereof.
EP 976382 describes a patch comprising a matrix composed of a system which is hydrophilically gelling in aqueous phase and which is formed from gelan gum and at least one further hydrocolloid. Gelan gum is claimed mandatorily. Gelan gum is understood by the skilled worker, as defined by technical dictionaries, to comprise hydrocolloids obtained from the following marine plants: Agardhiella tenera, Furcellaria fastigiata, Hypnea cervicornis, musciformis, spicifera, Suhria vitata. The term does not comprise sea algae extracts. Nor is there any mention of the essential aspects of self-adhesive properties, the adjustability of bond strength and elasticity of the resultant matrices.
A further problem associated with the cross-linking of polyacrylic acid to form a self-adhesive matrix or gel is that a matrix once produced, having defined physical properties, viscosity, tack, etc., must have the same defined properties in a later production operation. This reproducibility is difficult if not impossible to realize with the cross-linking technologies that are presently known.
It would be desirable to provide a simple polymer matrix system for cataplasms/hydrogels which, with a few ingredients, allows matrices of defined consistency and bond strength to be produced in a controlled fashion.
It would likewise be advantageous to be able to provide a polymer matrix in which water-soluble or hydrophobic active substances can be incorporated and can be delivered to the skin in a controlled fashion.
It would further be desirable to provide patches which comprise aforementioned polymer matrices and can be used as TTS.